A drug can have more than one harmful effect on the fetus. Individual effects depend on the time of fetal exposure to the drug. 

During the first 2 weeks after fertilisation and prior to full implantation, the embryo is thought to be resistant to any teratogenic effects of drugs. This is because there is no direct communication between maternal and embryonic tissue until after the placenta starts to form.

The critical period with respect to teratogenic effects is during organogenesis. This starts at about 17 days after conception and is complete by 60 to 70 days. Exposure to certain drugs during this period (17 to 70 days) can cause major birth defects.

Some drugs can interfere with functional development of organ systems (eg central nervous system, integumentary system, cardiovascular system) in the second and third trimesters and produce serious consequences.

It is quite possible that a woman may not be aware of her pregnancy until after the early stages of organogenesis. For this reason, drugs in the most severe category of risk (X in the Australian categorisation) should not be prescribed to a woman of childbearing potential, unless a pregnancy test is negative and she is using an effective method of contraception.

There are several conditions, however, in which long-term medication will be necessary in a woman of childbearing potential despite known risks of the drugs. At the time of initial prescribing in any such situation, the prescriber should discuss the desirability of reviewing medication requirements well before conception. For some disorders, it may be possible to change to a different category of drug. If a patient conceives while on medication and there has been no opportunity for prior discussion with the prescriber, her medication should be reviewed as soon as possible.

The following check list may assist in deciding whether to prescribe a particular drug during pregnancy:

Routine review later in the pregnancy includes consideration of whether dose alteration is indicated during delivery to avoid neonatal problems such as respiratory depression.

Pregnancy may represent an opportunity for the clinician to discuss the modification of maternal drinking and smoking behaviours. Every effort should be made to capitalise on a woman’s motivation to enter treatment during this time.

Educational and behavioural interventions are the mainstay of treatment. Pharmacological treatments should only be considered after specialist consultation.

Alcohol consumption during pregnancy is often associated with other risk factors, making alcohol-specific effects more difficult to identify. The major complication of substantial alcohol intake during pregnancy is the fetal alcohol syndrome (FAS) characterised by growth retardation, intellectual handicap, neurological damage and characteristic craniofacial abnormality. More moderate consumption of alcohol may be associated with fetal alcohol effects involving developmental delay and intellectual impairment.

Alcohol has also been associated with increased risk of spontaneous abortion. Some authorities believe that there is no safe level of alcohol consumption during pregnancy.

The safety of anticraving drugs such as naltrexone and acamprosate has yet to be established.

Approximately 23% of Australian women report having smoked during pregnancy. Such women often have higher prevalence of other risk factors (eg substance abuse, poor nutrition, noncompliance with antenatal care and a non-optimal living environment). Nevertheless, there is substantial evidence suggesting a causative link between smoking itself and several adverse outcomes. For many of these outcomes there appears to be a dose-dependent relationship with the number of cigarettes smoked. Mechanisms are less clear, but deficient oxygenation due to carboxyhaemoglobin and nicotine-induced uterine vasoconstriction appear to play a significant role. Recent literature has highlighted the potential importance of other harmful ingredients in cigarette smoke, apart from nicotine. 

The main adverse outcomes associated with smoking during pregnancy are:

It appears that up to 25% of Australian women smokers quit smoking without professional help when pregnancy is confirmed. However, this abstinence may not continue throughout the pregnancy, and many women resume smoking after delivery. 

The available evidence suggests that, in pregnant women, counselling may exert more influence on smoking than pharmacological interventions. Nicotine replacement therapy (NRT) during pregnancy remains controversial; however, there is an emerging consensus that the level of nicotine exposure to the fetus is less than that in women who continue to smoke heavily. Moreover, cigarette smoke is known to contain a large number of other potentially harmful ingredients, and these are avoided in successful NRT. The latter should be regarded as a possible adjunct to counselling. If NRT is utilised, care should be taken to ensure that the dose is minimised but consistent with the previous level of smoking. The woman should be warned that smoking while using nicotine patches is potentially dangerous, especially in women predisposed to vasospasm.

The safety of bupropion during pregnancy has yet to be established.

Recent studies suggest that the majority of pregnant women consume 100 to 300 mg of caffeine each day (brewed coffee contains 50 to 100 mg/100 mL; instant coffee and tea contains 20 to 70 mg/100 mL; cola drinks contain 10 to 20 mg/100 mL; caffeine tablets contain 200 mg and energy drinks average 30 mg/100 mL).

There is no evidence that moderate caffeine intake presents a teratogenic risk. However, caffeine has been linked to spontaneous miscarriage, preterm delivery and fetal growth retardation. This evidence is difficult to interpret because of the strong association between caffeine intake, smoking and alcohol intake. Nevertheless, when these confounders are controlled for, the available evidence suggests that intake in excess of 300 mg/day does increase the risk of these adverse outcomes.

There is no evidence of long-term neurobehavioural toxicity in children of women with moderate intake of caffeine in pregnancy.

Paracetamol is the analgesic of choice in pregnancy. Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided in late pregnancy. Aspirin will affect maternal platelet function and is associated with increased risk of prepartum and postpartum haemorrhage. Other NSAIDs could be expected to demonstrate these same effects. NSAIDs may also cause premature closure of the fetal ductus arteriosus and delay labour and birth. Women taking opioids chronically who become pregnant should let their obstetrician and their neonatologist know about the opioid use. They should probably be delivered in an appropriate tertiary hospital, where development in the neonate of a withdrawal syndrome will be prevented if possible, looked for, and managed as necessary. 

Topical application of therapeutic agents may lead to significant systemic absorption, the extent of which is influenced by factors such as: area and frequency of application; occlusion; absence of barrier function (eg in psoriasis); and region of application—drug absorption is higher from the face, intertriginous areas, perineum, and mucosal surfaces.

Increased drug concentration in the vicinity of the fetus resulting from the topical application of drugs to the genital mucosa of pregnant women should also be considered. 

A woman who has epilepsy and is taking antiepileptic medication has an increased risk of giving birth to an infant with an abnormality. This risk is about 2 to 3 times that of the general population and some of this risk is due to the antiepileptic drugs taken. Women taking more than one antiepileptic drug possibly have a higher risk of having a baby with a malformation.

All antiepileptic drugs are potentially teratogenic and there is no ‘drug of choice’ in pregnancy. However, many women with epilepsy need to be continued on antiepileptic drugs to prevent the potentially harmful effects of uncontrolled seizures to them, to their unborn child, and to others. In general, the best choice of treatment is the drug that best controls the epilepsy, at the lowest effective dose, in monotherapy if possible. Changes to the treatment regimen, including attempts to withdraw medications, are best done preconception.

Overall, the risk of teratogenicity is probably greatest with sodium valproate, particularly doses greater than 1200 mg/day, and phenobarbitone.

Sodium valproate has been associated with up to a ten-fold (0.2% to 2%) increased risk of spina bifida, as well as other serious malformations and coagulopathies. These effects are thought to be dose-related.

Carbamazepine has also been associated with significant increased risk of spina bifida in addition to developmental delay and craniofacial defects, although the risk is lower than with higher dose sodium valproate.

Data are now accumulating which suggest that lamotrigine (if taken alone) may not be associated with increased risk of congenital abnormalities if used in early pregnancy. Lamotrigine clearance may be increased by 50% in pregnancy requiring increased dose, with corresponding dose reduction after delivery (see below).

Phenytoin has been associated with distinctive craniofacial abnormalities, mental and growth deficiency and, less frequently, oral clefts and cardiac anomalies. 

Primidone, phenobarbitone or methylphenobarbitone, alone or in combination with other antiepileptic drugs, can cause coagulation defects in the neonate, which may be preventable by the administration of vitamin K to the mother prior to delivery.

The newer antiepileptic drugs, with the exception of lamotrigine, do not have enough data available to inform on their risk profile for birth defects, and therefore a decision on whether to continue these in a woman planning to become pregnant needs to balance the potential risk versus the potential benefit in seizure control.

Women taking antiepileptic drugs should be offered counselling (preferably preconception) and prenatal screening (alpha-fetoprotein measurement and ultrasound examination). If a decision is taken to continue antiepileptics, authorities suggest that the risk of neural tube defects may be reduced if larger than the standard dose of folic acid is taken prior to pregnancy (ie 5 mg/day instead of 0.5 mg/day) although this is not established to definitely reduce the risk. Phytomenadione (vitamin K1), taken from 36 weeks of pregnancy (20 mg/day ‘Konakion’ chewable tablets) has also been suggested to reduce the risk of coagulopathies in women using medications that induce the liver drug metabolising enzymes (eg carbamazepine, phenytoin, phenobarbitone).

Plasma antiepileptic drug concentrations may change during pregnancy, so concentrations should be measured preconception, during pregnancy, and over the first 3 months postpartum. Changes during and after pregnancy may be helpful in assessing the effect of the pregnancy on the woman’s pharmacokinetic profile for the drug, and therefore help guide decisions about dose adjustment. This is particularly important for lamotrigine, as the kinetics of lamotrigine are altered to such an extent that dose adjustments are usually required during pregnancy.

Lamotrigine plasma levels decrease in pregnancy because of increased hepatic drug clearance, which is induced by physiological changes during pregnancy. Studies have shown that the ratio of dose to plasma concentration is 5.8 times higher at delivery and 3.6 times higher in late pregnancy as compared with 5 months postpartum. 

It is recommended that a women’s plasma level of lamotrigine be measured prior to conception, or as early as possible into the pregnancy, so that a baseline can be established. Thereafter, the plasma levels of lamotrigine should be measured at least bimonthly throughout the pregnancy, and dose adjustments guided by plasma levels. Following parturition, maternal lamotrigine kinetics normalise in 2 to 3 weeks.

Ergotamine and the triptans should be avoided throughout pregnancy.

For acute treatment, paracetamol is safe but often inadequate for severe attacks. Many women have used aspirin and ibuprofen in early pregnancy but safety cannot be assured. Both aspirin and ibuprofen (but particularly aspirin) should not be used in late pregnancy, as these drugs may inhibit closure of the fetal ductus arteriosus; aspirin may also affect platelet function. Parenteral opioids, such as morphine, are probably safe but should be reserved for severe attacks. Repeated doses of pethidine can lead to the accumulation of a toxic metabolite, with resultant confusion and seizures. Repeated doses of opioids can lead to dependency and withdrawal symptoms in the mother and newborn.

For prophylaxis, propranolol and metoprolol have also been used but again safety cannot be assured. Beta blockers in late pregnancy may be associated with fetal bradycardia, hypoglycaemia and respiratory depression.

Azathioprine and cyclosporin can cross the placenta and cause immunosuppression in the neonate. Interferon beta-1b and methotrexate can induce spontaneous abortions.

Box 11.1 can provide a framework for the practitioner to address the decision whether or not to prescribe a psychotropic drug during pregnancy. It can also guide discussion with the woman, preferably in conjunction with her partner. 

A categorisation of harmful effects to the fetus has been developed utilising 5 classes as shown in Box 11.1. For classes 1 to 4 (death, congenital abnormality, growth retardation, neonatal toxicity), evidence (albeit of variable quality) is available for the more commonly used psychotropic medications. Class 5 (long-term neurodevelopmental effects) is largely unexplored, but should not deter prescribing where this is otherwise indicated. The relevance of the unknown risk in class 5 is to impress on the practitioner that no psychotropic can be considered 100% safe in pregnancy, nonpharmacological interventions always warrant consideration and unnecessarily high dosage and duration of treatment should be avoided. 

However, in relation to dosage, there are increases in total body water during pregnancy, as well as alterations in protein binding. Some pregnant women may require higher dosages of some medications (eg antidepressants) for an effective response.

Caution is warranted in prescribing only on the basis of preventing a condition (especially unipolar depression) which is not currently present (eg postnatal depression).

The safety of the atypical antipsychotics (amisulpride, clozapine, olanzapine, quetiapine, risperidone and ziprasidone) has yet to be established. However, on the basis of case reports and small series, there are no consistent reports of deleterious effects on the fetus. The most data is available for olanzapine and no increased risk has emerged. Isolated case reports of congenital abnormalities have been reported following clozapine use during pregnancy, but no definitive association has been established.

Unlike typical antipsychotics, some atypical antipsychotics (eg clozapine, quetiapine, aripiprazole) do not increase prolactin, and others (eg olanzapine) are less likely to increase prolactin, and hence are less likely to reduce women’s fertility. When changing from a typical to an atypical antipsychotic, warning women about this normalisation of their fertility is warranted. 

On the basis of the limited data available, these drugs appear to present no serious problems, with the possible exception of chlorpromazine, for which some evidence suggests a small increased risk of congenital abnormalities. However, larger doses of any of these drugs, especially when given continuously, may cause protracted withdrawal dyskinesias in the neonate.

Anticholinergics have Category B classifications and there is inconclusive evidence that they may have been associated with an increase in congenital abnormalities in some studies, as well as neonatal adverse effects. They should be avoided if possible in pregnancy. Beta-blockers may relieve akathisia, however possible cardiovascular adverse effects need to be taken into account. 

In the case of selective serotonin reuptake inhibitors (SSRIs), there is no evidence of increased malformation or growth retardation in humans; however, data are limited. If the patient is already on an SSRI and is well-controlled and becomes pregnant, the need for ongoing medication should be re-evaluated, however changing to another antidepressant is not indicated. 

Data on the safety of fluoxetine is more extensive than for other SSRIs. However, accumulating data on the latter pose no cause for concern at this stage. The very long half-life of fluoxetine (in the neonate) needs to be considered. Some authorities recommend reducing the dose of fluoxetine by 30% to 50% ten to fourteen days prior to delivery. However, the risk of relapse of depression has to be weighed against this.

Very recently, several reports have been published describing serotonergic effects in some neonates whose mothers were taking SSRIs prior to delivery. The true incidence of these effects remains unclear. Agitation/jitteriness, diarrhoea and poor feeding are the most consistent problems reported. Whether these are withdrawal or toxic effects remains uncertain. The problems have usually resolved in a few days, and none have lasted longer than 2 weeks. Paroxetine and fluoxetine have been associated with such effects in some neonates. However, the potential benefits of utilising shorter half-life SSRIs (in the lowest effective dose) in depressed pregnant women may well outweigh these short-term neonatal problems.

Preliminary data suggest venlafaxine is not associated with congenital abnormality. The safety during pregnancy of mirtazapine, moclobemide, nefazodone and reboxetine has not been adequately studied.

There is no evidence that exposure to tricyclic antidepressants (TCAs), even in the first trimester, carries any significantly increased risk of malformation. Many authorities still consider these antidepressants the drugs of choice in severe depression during pregnancy, on the grounds of the more extensive available evidence. Isolated case reports have suggested a possible increased risk with the use of doxepin, but this evidence is inconclusive. However, the prescriber needs to be aware of the much higher lethality in overdose of these antidepressants, compared to SSRIs. 

Some authorities regard nortriptyline as the TCA of choice during pregnancy due to its lower likelihood of anticholinergic adverse effects and orthostatic hypotension, as well as the ability to measure maternal serum levels.

In the neonate, anticholinergic adverse effects have occasionally been observed, as has a withdrawal reaction (irritability, insomnia, fever and colic). Abrupt discontinuation of clomipramine in pregnancy has been associated with premature delivery, and subsequent convulsions in the newborn. Case reports suggest that a single dose (mg/kg basis) of oral clomipramine for the newborn leads to cessation of convulsions by the third day.

The safety during pregnancy of mianserin and irreversible nonselective monoamine oxidase inhibitors (MAOIs) has not been adequately studied.

Discontinuation of 'mood stabilisers' in bipolar patients is associated with a significant risk of relapse. The risks versus benefits must be carefully weighed, taking into account the following sections on lithium and antiepileptics. 

The use of lithium within the first trimester has, in previous studies, been linked to fetal abnormalities. In particular, the risk of serious cardiac malformations was thought to be very significantly increased. Animal experiments have demonstrated marked teratogenic effects of lithium. More recent reviews have suggested that earlier estimates of risk in humans may have been overestimated, and at least one authority has concluded that the benefits of lithium prophylaxis during pregnancy may, in some cases, outweigh the risks. Nevertheless, most authorities still recommend against the use of lithium during pregnancy, although the risk of congenital heart defects may only be increased slightly. It has been suggested to avoid lithium until cardiogenesis is complete, ie about 50 days postconception, and then resume if necessary. 

In general, patients who are on lithium and who wish to become pregnant should have their lithium gradually withdrawn before conception occurs. If the pregnant patient develops symptoms and is in need of pharmacological treatment, then antidepressants and antipsychotic drugs can be prescribed for depressive or manic symptoms.

If a woman taking lithium wishes to conceive, the problem should be discussed with her. If a woman conceives while on lithium, the potential risks of illness recurrence after withdrawal of this medication must be balanced against the teratogenic risk to the fetus from lithium. If exposure has occurred in the first trimester, cardiac abnormalities can be investigated antenatally using ultrasound and echocardiography. These technologies have become increasingly specialised in recent years and expert advice should be sought.

Renal clearance increases during pregnancy and falls abruptly after delivery. Careful monitoring of serum lithium concentrations and dosage regimens is indicated. At delivery, lithium has been associated with the neonate being 'floppy' and less responsive. 

The puerperium is a time of high risk of relapse of mania or depression. Prophylactic treatment with lithium immediately after delivery is recommended by some authorities for patients with bipolar disorder who have been well-controlled on lithium. However, the implications for breastfeeding must also be considered (see Drugs used in bipolar disorder ('mood stabilisers')).

For information on antiepileptics, 

The issue of whether first trimester exposure to benzodiazepines is associated with increased risk of cleft lip and/or palate remains controversial. Pooled studies from prospective cohort studies have shown no increase in malformations. However, poorer quality, case-control studies have shown an association between exposure to benzodiazepines and major malformations or oral cleft alone. The first 8 weeks appears to be the period of highest risk. 

After the first trimester, anxious patients who do not respond to counselling or sleep hygiene measures may benefit from the intermittent use of low dose benzodiazepines as hypnotics. There is some evidence that oxazepam or temazepam, being shorter-acting drugs, are preferable to longer-acting benzodiazepines such as diazepam. 

If benzodiazepines are taken in late pregnancy, they can cause neonatal drowsiness, respiratory depression and hypotonicity (the floppy infant syndrome). Neonatal withdrawal symptoms have also been reported.

There are no available data to enable a definitive judgement to be made about the safety of zopiclone and zolpidem during pregnancy. However, evidence from small series suggests that zopiclone is not a major human teratogen. 

Neonatal withdrawal syndrome and low birthweight are immediate problems in the infants born to women receiving methadone for the management of opioid addiction. Increased stillbirth rates have also been noted. Caution is required during labour as methadone may cause respiratory depression in the newborn infant.

Buprenorphine is not currently recommended for use in pregnancy but case reports have not shown any adverse effects, and placental transfer appears less than that of methadone. There is emerging evidence that neonatal withdrawal in infants of women maintained on buprenorphine throughout pregnancy is substantially less than that associated with methadone.

There is no convincing evidence that any of the drugs commonly used to treat respiratory disorders cause any particular problems during pregnancy. As a general principle, the lowest dose achieving best control should be used. Inhalation has particular advantages as a means of drug administration during pregnancy because the therapeutic effect may be achieved without the need for plasma concentrations liable to have a pharmacological effect on the fetus.

Attacks of asthma during pregnancy may reduce the amount of oxygen available to the fetus, so it is particularly important that asthma should be well controlled. If this is achieved asthma has no important effects on pregnancy, labour or the fetus. Severe exacerbations should be treated promptly with conventional therapy. Asthma medications are very safe to use during pregnancy; prolonged courses of high-dose oral corticosteroids are an exception.

For a discussion of the issues involved in use of individual drugs or groups in pregnancy and in potential fathers,